There is a need for new systemic sclerosis subset criteria. A content analytic approach.

OBJECTIVES: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. METHODS: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. RESULTS: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). CONCLUSIONS: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).

[Nanna Svartz (1890-1986) : The first female professor of medicine in Sweden]. / Nanna Svartz (1890­1986) : Die erste Frau auf einem medizinischen Lehrstuhl in Schweden.

Nanna Svartz was a charismatic character who played a significant role in Swedish medicine in the mid-twentieth century. As one of five brothers and sisters, she escaped an early death from tuberculosis. She reached 96 years of age. Her diligence and sense of duty were legendary, along with her ambition to fully prove herself as "the first female professor". She inherited a certain insecurity from her father that led to her difficulty in taking criticism. Despite extensive academic obligations, she worked as a treating doctor for 55 years and always took her time with her patients, especially if they held important public positions. Nanna was honoured several times in her lifetime. Among others, she was a member of the Leopoldina, the National Academy of Germany, and received many honorary doctorates, for example, from Rockefeller College (USA) and the Åbo University (Turku, Finland). She was an honorary member of over 40 scientific societies. Underneath the new auditorium in the Karolinska Institute, a restaurant and a street in her home town of Västerås bear her name. An annual international Nanna Svartz Lecture is held by the Swedish Society for Rheumatology, and a Nanna Svartz Prize is awarded annually to a deserving young Swedish rheumatologist.

The IgA system. I. Studies of the transport and immunochemistry of IgA in the saliva.

1. Five patients with congenital or acquired agammaglobulinemia, lacking detectable IgA in serum or saliva, were transfused with 1 to 2 liters of normal plasma. In 2 of these patients IgA was demonstrated in parotid saliva collected after transfusion, but in none of the 5 was salivary IgG or IgM found. This observation indicates the selective transport of IgA into saliva. 2. The observation by others of an immunochemical difference between serum and sahvary IgA globulin was confirmed. In contrast to serum IgA, salivary IgA is attached to a protein having antigenicity which migrates as a gamma(1) globulin. We have termed this protein component "transport piece". 3. The transport piece has been found in an unbound form in the saliva of persons completely lacking IgA: agammaglobulinemic patients, ataxia-telangiectasia patients, a healthy person lacking IgA, and a newborn infant. Free transport piece still occurs in the normal child's saliva after IgA production begins. By adulthood there is usually no free transport piece in the saliva. 4. Heat-aggregated salivary IgA, like heat-aggregated serum IgA, does not fix complement. 5. Our findings offer support for the view that there is a distinct local antibody system for the protection of the mucous surfaces.

Effects of sulindac and naproxen on prostaglandin excretion in patients with impaired renal function and rheumatoid arthritis.

PURPOSE: The purpose of the current investigation was to study the influence of sulindac and naproxen on renal function and urinary excretion of the stable hydration product of prostacyclin, 6-keto-PGF1 alpha, in patients with arthritis and impaired renal function. PATIENTS AND METHODS: In a placebo-controlled, double-blind, cross-over design, the effects of 7 days of oral sulindac 200 mg twice a day were compared with naproxen 500 mg in the morning and 250 mg in the evening in 10 patients with polyarthritis and stable impaired renal function. Inulin and para-amino-hippurate sodium were used to calculate glomerular filtration rate and renal plasma flow. The excretion rate of 6-keto-PGF1 alpha was measured in urine collected overnight. After patients ingested drugs in the morning, urine was collected in fractions by spontaneous voiding. Venous blood samples were drawn repeatedly for assay of electrolytes, creatinine, proteins, hormones, and drugs. Grip strength and Ritchie articular index were recorded as indicators of symptomatic antiarthritic effectiveness. RESULTS: Naproxen decreased urine levels of 6-keto PGF1 alpha by 59% (p less than 0.01). Sulindac had no effect on renal prostaglandin excretion. Naproxen reduced the glomerular filtration rate and renal plasma flow by 18% (p less than 0.05) and 13% (p less than 0.05), respectively, while no significant change was observed during the sulindac treatment periods. Serum levels of creatinine and complement factor D were unaffected by either drug. Plasma renin activity decreased during naproxen and sulindac treatments by 38% (p less than 0.05) and 22% (p less than 0.05). No significant change in plasma aldosterone was observed during the two drug treatments, but urinary aldosterone declined significantly (p less than 0.05) by 34% with naproxen. Albuminuria decreased (p less than 0.05) during both naproxen (41%) and sulindac treatment (72%), while the albumin/creatinine clearance ratio decreased by 59% (p less than 0.05) only during treatment with sulindac. N-acetyl-beta-D-glucosaminidase in urine was not changed by either drug. Sulindac and naproxen had no discernible effects on base excess, excretion of water, sodium, or potassium, or on osmolal clearance. However, serum potassium increased slightly but significantly (p less than 0.01) during treatment with naproxen. Sulindac sulfide, the active metabolite of sulindac, could not be traced in the urine from any of the patients. Mean arterial blood pressure declined significantly (p less than 0.05) during sulindac treatment but did not change during treatment with naproxen. Both drugs produced equal clinical improvement as measured by grip strength and the Ritchie articular index. CONCLUSION: The results suggest that when sulindac and naproxen are given in clinical equipotent doses to patients with impaired renal function, sulindac does not affect renal prostaglandin synthesis or renal function, whereas naproxen induces suppression of renal prostaglandin synthesis and a further decrease in renal function.

Current pharmacological treatment of osteoarthritis.

In this overview, the currently available symptomatic treatments of osteoarthritis from the published literature are evaluated. Paracetamol attracts growing interest as a less toxic yet potent alternative to NSAIDs. These latter agents are, however, used more widely than paracetamol, although adverse reactions associated with their use are of increasing concern among both patients and physicians. New NSAIDs are still under development. While there is not much evidence of important differences between NSAIDs in overall efficacy, they do vary with regard to toxicity. The cytoprotective effect of misoprostol in at-risk patients on NSAIDs is established but the cost-effectiveness is unclear. Furthermore, percutaneous administration of NSAIDs, capsaicin, and other substances may have some merit. Opioids, such as dextropropoxyphene, are used in combination with paracetamol in patients intolerant to NSAIDs or when pain is not controlled with NSAIDs. Locally administered glucocorticoids may have a disease-modifying effect and are of symptomatic use in certain situations. The role, if any, of hyaluronan therapy remains to be established. Although this agent appears to have a good safety profile, it is expensive. Chondroprotection is an interesting field for future research, although there is no good evidence supporting its existence in clinical medicine as practised now.

Predictors of joint damage in rheumatoid arthritis.

Rheumatoid arthritis (RA) is the dominant form of destructive chronic arthritis with the potential to cause substantial disability and permanent functional impairment. The final extent and progression rate with time, however, varies markedly. In order to study effects of intervention and to support early aggressive and atoxic therapy in selected cases, predictive disease markers are needed. Recent advances regarding joint tissue composition and pathophysiology have defined a number of biological marker candidates which need to be explored for possible prognostic information. Some markers are characteristic for RA, such as rheumatoid factors and certain autoantibodies, which although they are more prevalent among patients with aggressive disease are not sensitive as predictors in early disease. Genetic susceptibility markers have been claimed to be good predictors of persisting arthritis in early synovitis clinics, but their role as severity markers in established disease is limited. Unspecific markers of inflammation, notably ESR or CRP when persistently elevated, are useful to monitor disease course and newer markers need to document their superiority over these. Another group of markers are attractive because of enriched or exclusive occurrence in joint tissue, and altered metabolism in joint disease. Thus, collagen type III propeptides, hyaluronates, and neopterin originating in the synovium could be useful, and, in particular, hyaluronate levels indeed do provide some predictive information. Highly tissue-specific cartilage metabolites include aggrecan fragments, collagen II fragments, cartilage oligomeric matrix protein (COMP) and the extraarticular cartilage matrix protein (CMP). When used alone or in combination in early disease some information can be obtained which may in the future facilitate prognostication. Bone metabolism can be monitored and there are different markers for synthesis and resorption. Meanwhile, whilst the new markers are essential research tools, their routine clinical usefulness remains to be proven.

Serum markers of articular cartilage damage and repair.

Joint cartilage is a dynamic tissue that reacts to trauma, inflammation, and other insults by attempting to repair its matrix. This reaction results in the release of cartilage macromolecules into the body fluids. Analysis of these fluids has identified a limited number of at least somewhat tissue-specific markers of altered cartilage metabolism. Analyses of serum are less specific and less sensitive than analyses of synovial fluid, but their use as research tools in clinical studies, drug development, and experimental work in animal models is increasing.

A problem-based education program for patients with rheumatoid arthritis: evaluation after three and twelve months.

OBJECTIVE: To develop and evaluate the effect of a new arthritis education program based on a previous study. METHODS: One hundred individuals with established rheumatoid arthritis randomized to an intervention group or a control group completed self-report questionnaires. RESULTS: Three months after the education program the patients in the intervention group had increased their knowledge about their disease. They reported increased practice of exercise and joint protection and reduction of disability and pain. After 12 months, increased knowledge and practice of joint protection was maintained. However, there was no longer any difference between the intervention group and the control group regarding reported pain, disability, and practice of exercise. At both intervals the individuals in the intervention group reported an increased ability to handle their pain and a reduction of problems with their disease. The control group remained stable except for a slight increase in pain. CONCLUSION: A structured patient education program had positive impact for 3 months, and some improvements were maintained for 12 months. We suggest that patient education should become an integrated part of the total management of rheumatoid arthritis.

Inhibition of in vivo leucocyte migration by NSAIDs.

Leucocyte migration was studied in vivo using a skin window technique, and in vitro by migration under agarose. No difference was found between 28 patients with rheumatoid arthritis (RA), 10 patients with psoriatic arthritis (PA) and 30 healthy controls. Most patients were under treatment with anti-rheumatic drugs. Patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) had significantly lower values (p less than 0.01) than untreated patients. In vivo but not in vitro migration decreased during short-term treatment with diclofenac and naproxen, an effect observed both in patients and in healthy individuals. After pre-incubation of normal polymorphonuclear leucocytes with diclofenac, in vitro migration was diminished only at concentrations of 50 micrograms/ml and above, which are at least 10 times higher than those attained clinically. The in vivo effect of NSAIDs on leucocyte migration may imply a long-term disease modifying influence in chronic arthritides.

No effect of acetylcystein on refractory rheumatoid arthritis.

Acetylcystein has some chemical similarities with Penicillamine and other thiol containing compounds with effect on rheumatoid arthritis. We report an open trial on seven patients with refractory rheumatoid arthritis in which no beneficial effect could be seen after up to twelve months treatment in doses 600-1200 mg acetylcystein daily. No definite laboratory changes were seen, apart from a tendency towards higher IgA levels at the end of the treatment period.

Alkaptonuria and ochronosis in three siblings. Ascorbic acid treatment monitored by urinary HGA excretion.

Patients with alkaptonuria lack homogentisate 1,2-dioxygenase leading to retention of homogentistic acid (HGA) in body fluids and eventually to tissue deposition of oxidation products, giving rise to the clinical picture of ochronosis. Ascorbic acid is a known inhibitor of the enzyme which catalyses the oxidation of homogentisic acid (HGA) to the polymer with affinity for collagen and was used in the treatment of three siblings with alkaptonuria. Ascorbic acid 500 mg bid was administered for 12 months. Two of the siblings tolerated the treatment, and in one the symptoms improved, whereas in the other they worsened. Plasma and urinary levels of HGA were monitored with a new HPLC method. Ascorbic acid is not effective in the treatment of symptomatic ochronosis.

Hyaluronidase treatment of synovial fluid affects the recovery of mononuclear cells and their in vitro immunoglobulin synthesis.

Treatment of arthritic synovial fluid with hyaluronidase reduced the recovery of mononuclear cells as well as their in vitro IgA and IgG synthesis. Hyaluronidase should be avoided in the treatment of synovial fluid when unselected mononuclear cell populations are required.

Reduced in vivo leucocyte migration and elastase and lysozyme concentrations in skin chamber experiments with piroxicam in healthy volunteers.

Leucocyte migration in vivo, studied with a skin chamber technique was inhibited in eight healthy volunteers after six days' medication with piroxicam, 20 mg a day, but not after only one day's medication. The inhibition was not correlated to the serum content of the drug. The median trough values of piroxicam in serum were 2.5 mg/l and in blister fluid 1.2 mg/l after six days' medication. Leucocyte migration in vitro under agarose was not inhibited after six days' medication with piroxicam. When normal polymorphonuclear leucocytes were incubated with piroxicam in vitro migration under agarose was inhibited but only at piroxicam concentrations higher than those attainable in clinical therapy. The concentrations of elastase and lysozyme in the skin chamber decreased after six days' medication with piroxicam.

D-penicillamine in early rheumatoid arthritis: experience from a 2-year double blind placebo controlled study.

OBJECTIVE: To evaluate the usefulness of early treatment with D-Penicillamine (DPA) in rheumatoid arthritis. METHODS: The patients were recruited from a Swedish early RA cohort comprising 180 patients. All patients experiencing active and/or erosive disease 2 years from onset were asked to participate in a 2-year placebo-controlled DPA trial. Previous treatment with slow-acting anti-rheumatic drugs (SAARDs) or oral corticosteroids was not allowed. The main outcome variable was radiographic progression in the hands and feet evaluated according to Larsen. Clinical assessment including the Ritchie index, active joint count, and the HAQ-disability index was performed every 6th month. Patients were included in the analyses of efficacy until the endpoint of therapy. RESULTS: 111/180 patients were eligible for treatment, and 74 agreed to participate in the trial. 21/33 patients on DPA and 22/41 on placebo completed the study. More patients taking placebo stopped due to lack of response (p < 0.01). 27% of the patients on DPA were withdrawn due to side effects. Radiographic deterioration increased but most clinical variables improved in both trial arms. A large inter-individual variation was observed. The only significant difference in trend over 2 years between DPA and placebo was found for joint tenderness. However, the median trends for most clinical variables showed a more positive effect for DPA. The 37 patients who refused to participate in the trial in general fared somewhat worse than patients taking DPA and somewhat better than patients taking placebo. The remission rate was about the same in all 3 groups (12-13.5%). CONCLUSIONS: About two-thirds of all early definite RA patients were eligible for treatment using current criteria. Psychological readiness for early therapy was fairly modest with a high refusal rate. The difference in efficacy between DPA and placebo was small, but was in favour of DPA for most clinical variables. However, only joint tenderness showed a significantly better trend. No significant slowing of radiographic progression by DPA was found.

The attachment of certain gram negative bacteria to buccal epithelial cells from patients with Yersinia arthritis.

The frequency of attachment of certain members of the Enterobacteriaceae implicated in arthritis to buccal epithelial cells from patients with post-Yersinia reactive arthritis, Yersinia enteritis and from healthy controls was examined using a fluorescent labelling technique. Klebsiella K43 bound significantly more frequently to cells from reactive arthritis patients compared healthy controls (2 p less than 0.05) and after incubation overnight at 37 degrees C this binding increased still further. In addition, under these conditions Escherichia coli bound more frequently to arthritis cells as compared with controls (2 p less than 0.01). Upon examination for the presence of HLA B27. Yersinia 03 was found to bind significantly more frequently to B27 positive reactive arthritis patients compared with B27 negative individuals when the bacteria and cells were incubated overnight at 37 degrees C (2 p less than 0.01).

Protease inhibitors in rheumatoid synovial fluid: a quantitative analysis.

The concentrations of the main endogenous inhibitors of granulocyte proteases (anti-leukoprotease, alpha 1-antitrypsin, alpha 1-antichymotrypsin, and alpha 2-macroglobulin) were estimated in paired samples of synovial fluid and serum/plasma from seropositive rheumatoid arthritics and controls. Rheumatoid synovial fluid contained significantly higher levels of all inhibitors except antileukoprotease. The influence of the synovial membrane on these concentrations was taken into account by comparing the ratio between the observed concentration and that predicted from a certain regression curve fitted to a set of non-inhibitory reference proteins of extra-articular origin (orosomucoid, albumin, and ceruloplasmin). Divergences were interpreted as the net result of intra-articular production or consumption of the inhibitor in question. The results suggested a consumption of antileukoprotease and alpha 1-antitrypsin in the rheumatoid joint, while the increased levels of alpha 1-antichymotrypsin and alpha 2-macroglobulin probably reflected the altered trans-synovial membrane protein flux with some reservation for alpha 2-macroglobulin.

Serum aminoterminal type III procollagen peptide in early rheumatoid arthritis: relation to disease activity and progression of joint damage.

Serum levels of the aminoterminal type III procollagen peptide (S-PIIINP) have been used as markers of proliferative inflammation in rheumatoid arthritis (RA) and a prognostic significance has been suggested. To test this further we have measured S-PIIINP longitudinally for 2 years in 66 patients with definite RA and a disease duration of less than 2 years, and related the levels to clinical, biochemical, and radiographic findings. In this patient group the correlations between S-PIIINP and ESR and CRP, respectively, were higher than those obtained between S-PIIINP and articular indices, and markedly higher than in patients with RA of longer duration. Patients with normal mean levels of S-PIIINP during the study period had a significantly slower rate of radiographic progression than patients with elevated mean levels of S-PIIINP. ESR yielded in general higher correlations with the joint damage process than did S-PIIINP. The correlations between S-PIIINP and the joint damage scores increased with time. A multiple regression analysis showed that ESR explained most of the variance in joint damage progression over 2 years, but S-PIIINP added independent information. About one third of the variance could be explained by the two variables.

Cineradiography identifies esophageal candidiasis in progressive systemic sclerosis.

Cineradiography of the esophagus showed signs of esophageal candidiasis in 11 out of 71 patients with progressive systemic sclerosis (PSS) - both in diffuse scleroderma and the CREST syndrome. Culture of esophageal brushings confirmed the presence of Candida albicans in eight of these 11 patients. Antimycotic treatment decreased the cineradiographic signs of candidiasis and the degree of dysphagia. Since impaired esophageal motility and treatment with immunosuppressive drugs may predispose to candida esophagitis, and since dysphagia will decrease after antimycotic treatment esophageal mycosis should always be sought in patients with PSS.

Gastrointestinal function in patients with progressive systemic sclerosis.

In 24 patients with progressive systemic sclerosis (PSS) the pentagastrin-stimulated gastric acid secretion was determined to investigate if acid hypersecretion is associated with reflux-oesophagitis--the most common complication to oesophageal involvement in PSS. Gastro-oesophageal reflux was observed in 12, reflux-oesophagitis in 9 and oesophageal mycosis in 8 patients. Gastric acid secretion was increased in 13 (54%) patients and tended to be higher in patients with oesophagitis. Patients with reflux and increased acid secretion seemed to be free from oesophageal mycosis. Bacterial overgrowth and malabsorption are known complications to intestinal scleroderma and these items were investigated using non-invasive methods. Four patients had increased bile acid deconjugation, 3 had increased (14C)xylose degradation indicating bacterial overgrowth and 7 patients had decreased fat absorption in the triolein breath test. Nutritional status with respect to selenium, folate, cobalamin and fat-soluble vitamins was essentially normal.

Rapidly progressing rheumatoid arthritis: an example of polyclonal B-cell activation?

We report the case of a 76-year old woman who presented with a palindromic onset of seropositive rheumatoid arthritis. After suffering from a fulminant pulmonary infection she developed serologic tests for ornitosis, mycoplasma, pneumocystis carinii and low titer yersinia. Also the rheumatoid factor titer increased and the antinuclear antibody test became positive. Clinically, the course of a rather benign polyarthritis changed into a rapidly progressive deforming disease. The course was also complicated by cutaneous necrotizing vasculitis. Further deterioration occurred after a relapse of pulmonary infection, and she died following acute abdominal surgery for perforated sigmoiditis. It is speculated that the clinical course was in part caused by polyclonal B-cell activation.